title: A diametric role for OX40 in the response of effector/memory CD4+ T cells and regulatory T cells to alloantigen.
abstract: OX40 is a member of the TNFR superfamily that has potent costimulatory properties. Although the impact of blockade of the OX40-OX40 ligand (OX40L) pathway has been well documented in models of autoimmune disease, its effect on the rejection of allografts is less well defined. In this article, we show that the alloantigen-mediated activation of naive and memory CD4(+) T cells results in the induction of OX40 expression and that blockade of OX40-OX40L interactions prevents skin allograft rejection mediated by either subset of T cells. Moreover, a blocking anti-OX40 had no effect on the activation and proliferation of T cells; rather, effector T cells failed to accumulate in peripheral lymph nodes and subsequently migrate to skin allografts. This was found to be the result of an enhanced degree of cell death among proliferating effector cells. In clear contrast, blockade of OX40-OX40L interactions at the time of exposure to alloantigen enhanced the ability of regulatory T cells to suppress T cell responses to alloantigen by supporting, rather than diminishing, regulatory T cell survival. These data show that OX40-OX40L signaling contributes to the evolution of the adaptive immune response to an allograft via the differential control of alloreactive effector and regulatory T cell survival. Moreover, these data serve to further highlight OX40 and OX40L as therapeutic targets to assist the induction of tolerance to allografts and self-Ags.
authors.affiliation: Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
authors.forename: Gillian
authors.initials: G
authors.lastname: Kinnear
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wood
authors.forename: Farnaz
authors.initials: F
authors.lastname: Fallah-Arani
authors.forename: Nick D
authors.initials: ND
authors.lastname: Jones
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D018398:Homeodomain Proteins / Q000235:genetics; D007108:Immune Tolerance; D007156:Immunologic Memory; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D053278:OX40 Ligand; D053262:Receptors, OX40 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D007519:Isoantigens; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; C064658:RAG-1 protein